Effects of cardiovascular (CV) treatments on chronic obstructive pulmonary disease (COPD)
| Author/study | Design and participants | Duration | Population | Treatment(s) | Primary outcome | Key results | Other findings |
| β-blockers | |||||||
| Dransfield (2008) [97] | Retrospective, cohort (University of Alabama Hospital) (n=825) | Discharge or death summaries indicated primary diagnosis of AECOPD or primary diagnosis of ARF and secondary diagnosis of AECOPD | Users of β-blockers (n=142) Non-users (n=683) | In-hospital mortality | β-blocker use was associated with a reduction in mortality (OR 0.39, 95% CI 0.14–0.99) A significant association was observed between daily β-blocker doses and mortality (OR 0.31, 95% CI 0.12–0.80) | SABA use was also associated with a reduction in mortality (OR 0.39, 95% CI 0.14–0.99) | |
| Rutten (2010; Utrecht GP Network Database) [98] | Observational, cohort (n=2230) | Individuals aged ≥45 years with an incident or prevalent diagnosis of COPD | β-blockers | All-cause mortality First COPD exacerbation | β-blocker use was associated with: 1) A reduction in mortality (HR 0.68, 95% CI 0.56–0.83) 2) A reduction in exacerbations (HR 0.71, 95% CI 0.60–0.83) | Subgroup analyses revealed that patients with COPD but without overt CVD had similar results | |
| Short (2011) [99] | Retrospective, cohort (NHS Tayside Respiratory Disease Information System) (n=5977) | Diagnosis of COPD (GOLD guidelines) | Respiratory and CV drugs | Mortality COPD-related hospital admissions | β-blocker use was associated with: 1) A 22% reduction in all-cause mortality versus no β-blocker use 2) Reduction in mortality from MI (HR 0.67, 95% CI 0.41–1.10) and COPD (HR 0.88, 95% CI 0.32–2.38) 3) Reduced risk of respiratory-related hospital admissions (HR 0.31, 95% CI 0.22–0.44) | ||
| Stefan (2012) [100] | Retrospective, cohort (Perspective Inpatient Administrative Database (Premier Inc, Charlotte, NC, USA), 404 hospitals) (n=35 082) | Individuals aged ≥40 years with a principal diagnosis of AECOPD, or a principal diagnosis of respiratory failure and a secondary diagnosis of AECOPD or emphysema, and with a secondary diagnosis of IHD or HF | β-blockers Treatment with inhaled β2-agonists and systemic corticosteroids on the first or second day of the hospitalisation | In-hospital mortality | No association between β-blocker therapy and: 1) In-hospital mortality (OR 0.88, 95% CI 0.71–1.09) 2) 30-day readmission (OR 0.96, 95% CI 0.89–1.03) 3) Late mechanical ventilation (OR 0.98, 95% CI 0.77–1.24) | 25% increased odds of 30-day readmission (OR 1.25, 95% CI 1.08–1.44) with nonselective β-blocker versus β1-selective β-blocker | |
| Du (2014) [101] | Meta-analysis (15 observational, cohort studies) (n=121 956) | 1–7.2 years | Individuals with COPD | β-blockers | Mortality | β-blocker use was associated with: 1) A reduction in COPD exacerbations (rate ratio 0.63, 95% CI 0.57–0.71) 2) A reduction in the risk of overall mortality (rate ratio 0.72, 95% CI 0.63–0.83) | |
| Puente-Maestu (2014) [102] | Analytical, cross-sectional (n=256) | Individuals with previous COPD diagnosis and CHF/CAD diagnosis ≥1 year prior to baseline who meet the criteria for β-blocker treatment with no contraindications | β-blocker | Lung function ECG LVEF Haemoglobin concentrations Heart rate Exacerbations Hospital admissions CAT Comorbidities | β-blocker use was associated with: 1) Fewer COPD patients experiencing exacerbations requiring ER visits (36.9% versus 58.8% among patients without β-blockers, p<0.000) 2) Fewer COPD patients experiencing ≥2 exacerbations or ER visits (38.8% versus 58.8% among patients without β-blockers, p<0.000) | ||
| Bhatt (2016; follow-up of the COPDGene cohort) [103] | Prospective, follow-up (n=3464) | 2.1 years median follow-up | Individuals diagnosed with GOLD stage 2 to 4 COPD | β-blocker CCB ACEI/ARB | Exacerbation rate (total and severe) | β-blocker use was associated with a reduction in the rate of total exacerbations (IRR 0.73 (95% CI 0.60–0.90), p=0.003) and severe exacerbations (IRR 0.67 (95% CI 0.48–0.93), p=0.016) In individuals with GOLD stage 3 and 4, β-blocker use was associated with a reduction in the rate of total exacerbations (IRR 0.33 (95% CI 0.19–0.58), p<0.001) and severe exacerbations (IRR 0.35 (95% CI 0.16–0.76), p=0.008) | |
| Key (2017) [104] | Cohort, cross-over (n=48) | Individuals were aged ≥18 years and able to perform a cardiopulmonary exercise test | β-blocker | Lung function | β-blocker use led to a small reduction in FEV1 compared with non-use | ||
| RAAS blockers (ACEIs, ARBs) | |||||||
| Kanazawa (2003) [105] | Randomised, double-blind, placebo-controlled, crossover, pilot (n=36) | Males with COPD (ACE genotypes II (n=13), ID (n=11), DD (n=12)) | Captopril 25 mg·day−1 Placebo | Pulmonary haemodynamics (mean PAP, PVR, lactate concentration and PvO2) | Mean PAP, PVR and lactate concentration after exercise were lower for captopril than placebo in patients with the genotypes II or ID | PvO2 after exercise was higher with captopril versus placebo in patients with genotype II | |
| Andreas (2006) [106] | Randomised, double-blind, placebo-controlled (n=60) | 4 months | Patients with COPD (FEV1 <50% pred) Aged 30–80 years | Irbesartan 150 mg·day−1 (increased to 300 mg·day−1 after 4 weeks) (n=30) Placebo (n=30) | Lung function (PImax) | Irbesartan did not affect PImax (baseline: 4.8 kPa; 4 months: 4.5 kPa) | Irbesartan reduced: 1) TLC (baseline: 119.7% pred; 4 months: 113.7% pred; p=0.01) 2) Haematocrit (from 46.4% to 43.9%, p<0.0001 versus placebo) |
| Parikh (2017) [124] | Population-based cohort study (as part of the Multi-Ethnic Study of Atherosclerosis) (n=4472) | 9.3 years median follow-up | Participants aged 45–84 years from the general population (3% had emphysema at baseline) | ACEIs ARBs | Percent emphysema (percentage of lung regions less than −950 Hounsfield units on CT scans) | Higher doses of ACE or ARB were independently associated with a slower change in percent emphysema (p=0.03). Over 10 years, the predicted mean increase in participants who used maximum doses of ARBs or ACEIs was 0.06 percentage points versus 0.66 percentage points in those who did not take ARBs or ACEIs (p=0.01) | The findings were of greatest magnitude among former smokers (p<0.001) |
| Lai (2018) [122] | Population-based cohort (Taiwan National Health Insurance Database) (n=12 452) | 6–11 year follow-up | Patients with COPD aged ≥40 years who received prescriptions for an ACEI or ARB for >90 days between 2000 and 2005 Allocated to ACEI (n=6226) and ARB (n=6226) cohorts | ACEIs ARBs | Pneumonia Severe exacerbations (COPD-related hospitalisation or ER visit) Mortality | Patients treated with ACEIs had significantly higher rates of severe COPD exacerbations (adjusted rate ratio 1.22, 95% CI 1.15–1.29) and a higher risk of pneumonia (adjusted HR 1.22, 95% CI 1.15–1.29) than those in the ARB group | ARBs were also associated with a lower risk of pneumonia requiring mechanical ventilation (adjusted HR 1.35, 95% CI 1.24–1.47) and of mortality (adjusted HR 1.33, 95% CI 1.26–1.42) |
| Statins | |||||||
| Mancini (2006) [107] | Retrospective, time-matched nested case–control (Quebec Linked Databases) (n=19 720) | Two cohorts (aged ≥65 years) as follows: 1) Revascularised patients with high CV risk (n=946 cases; n=18 774 controls) 2) General population of NSAID users without previous MI (n=4907 cases; n=98 097 controls) | Statins ACEIs ARBs | COPD hospitalisation MI Mortality | Statin use was associated with reduced risk for COPD hospitalisation (p=0.0091) and with the combined use of statins and ACEIs or ARBs (p=0.0012) Risk ratios for MI were reduced by all three drug classes, particularly by the combination of statins with ACEIs or ARBs (p<0.0001) Death risk ratios were reduced by ARBs (p=0.0010), statins (p<0.0001) and statins with ACEIs or ARBs (p<0.0001) | Similar benefits were observed when steroid users were included in the analysis | |
| Alexeeff (2007; Veterans Administration normative study) [108] | Longitudinal (n=803) | 10 year follow-up | Elderly men with no prior known medical conditions | Statins | Lung function (FEV1, FVC) | Estimated decline in FEV1 was lower in patients using statins than those not using statins (10.9 mL·year−1 versus 23.9 mL·year−1, respectively) Estimated decline in FVC was lower in patients using statins than those not using statins (14 mL·year−1 versus 36.2 mL·year−1, respectively) | There was a significant three-way association between time since first visit, statin use and smoking status (p<0.001) |
| Lee (2009) [109] | Randomised, double-blind, parallel group (n=53) | 6 months | Patients with COPD and PH aged 40–80 years FEV1 <80% pred FEV1/FVC <70% | Pravastatin 40 mg·day−1 (n=27) Placebo (n=26) | Change in exercise time from baseline to 6 months | Exercise time significantly increased from baseline with pravastatin (52% at 6 months, from 660 s to 1006 s; p<0.0001) | Pravastatin was associated with less dyspnoea after exercise versus placebo (Borg dyspnoea score decreased from 6.7 at baseline to 3.86 at 6 months with pravastatin versus 6.9 to 6.8 with placebo; p<0.05) |
| Mortensen (2009) [110] | Retrospective national cohort (VA administrative data) (n=11 212) | Patients (98% male) aged >65 years hospitalised with COPD exacerbation and received one or more respiratory medications# within 90 days of presentation | Users of statins or ACEIs/ARBs (n=4711) Non-users (n=6501) | 90-day mortality | Statin use associated with significantly reduced 90-day mortality (OR 0.51, 95% CI 0.40–0.64) | ACEI/ARB use associated with significantly reduced 90-day mortality (OR 0.55, 95% CI 0.46–0.66) | |
| Bartziokas (2011) [111] | Prospective follow-up (n=245) | 12 months | Patients with COPD admitted to hospital for COPD exacerbations | Statins | 30-day or 1-year mortality | Statins had no effect on 30-day or 1-year mortality | Statins were associated with a lower risk for COPD exacerbations (HR 0.656, 95% CI 0.454–0.946) and severe exacerbations (HR 0.608, 95% CI 0.381–0.972) |
| Huang (2011) [112] | Population-based cohort (Taiwan National Health Insurance Database) (n=18 721) | 4.58 year mean follow-up | Patients newly diagnosed with COPD (median age 64 years) receiving statins for hyperlipidaemia | Statins (n=6252) Control (n=12 469; matched for age, sex and COPD treatment (non-statin users)) | Hospitalisation for COPD | Fewer patients in the statin group (n=508, 8.1%) were hospitalised for COPD exacerbation versus the control group (n=1324, 10.6%; p<0.001) | Statin use was associated with decreased risk of COPD hospitalisation (HR 0.66 (95% CI 0.60–0.74), p<0.001) |
| Bando (2012; Japan) [113] | Observational, cross-sectional (n=853) | Outpatients ≥40 years who regularly visited a primary healthcare facility | Statins | Lung function | The prevalence of airflow limitation was lower among patients with a history of statin use than those who had not used statins (2.3% versus 10.5%, respectively) Statin use was not significantly associated with a lower prevalence of airflow limitation | Airflow limitation was not observed in patients with a history of smoking who had used statins | |
| Wang (2013) [114] | Retrospective nested case–control (nationwide health insurance claims database, Taiwan) (n=14 316) | Patients with COPD hospitalised for COPD exacerbations (n=1584) matched to 5950 controls | Statins | COPD exacerbation | Current use of statins associated with a 40% decreased risk of COPD exacerbation (OR 0.60, 95% CI 0.44–0.81) | Statins reduced risk of COPD exacerbations in a dose-dependent manner (medium average daily dose: OR 0.60, 95% CI 0.41–0.89; high daily dose: OR 0.33, 95% CI 0.14–0.73) | |
| Lahousse (2013; Rotterdam Study) [115] | Nested case–control (n=7983) | 363 patients with COPD who died during follow-up versus 2345 age-/sex-matched COPD controls | Statins | Mortality | Long-term statin use (>2 years) was associated with a 39% decreased risk of death | Long-term statin use was associated with 78% reduced mortality with hsCRP >3 mg·L−1 (versus 21% reduction for hsCRP ≤3 mg·L−1) | |
| Criner (2014; STATCOPE) [116] | Multicentre, randomised, parallel group, placebo-controlled (n=885) | Up to 36 months (mean follow-up ∼21 months) | Patients 40–80 years old with moderate-to-severe COPD (post-bronchodilator FEV1/FVC <70% and FEV1 <80% pred) and smoking history ≥10 pack-years COPD exacerbation in the previous year¶ | Simvastatin 40 mg once daily (n=433) Placebo (n=452) | Exacerbation rate (number of exacerbations per person-year) | No significant difference in mean exacerbation rate between simvastatin and placebo (1.36 versus 1.39 exacerbations per person-year, respectively) | Median days to first exacerbation was similar for simvastatin (223 days) and placebo (231 days) |
| Ingebrigtsen (2015; Copenhagen General Population Study) [117] | Nested case–control (n=5794) | 3 year follow-up | Individuals with COPD and CRP measurement matched for age, sex, smoking, COPD severity and comorbidity | Statins | COPD exacerbations | Statins associated with reduced risk of COPD exacerbations (crude analysis: OR 0.68 (95% CI 0.51–0.91), p=0.01; multivariate analysis: OR 0.67 (95% CI 0.48–0.92), p=0.01) | In a subgroup of patients with the most severe COPD and no CV comorbidity, statins did not reduce risk of COPD exacerbations (OR 1.1, 95% CI 0.5–2.1) |
| Rossi (2017; GISSI-HF) [118] | Randomised, double-blind, placebo-controlled (n=1060) | Rosuvastatin 10 mg (n=538) Placebo (n=522) | All-cause mortality | There was no significant difference in all-cause mortality between rosuvastatin and placebo (p=0.30) | There were no significant differences in CV death (p=0.88), non-CV death (p=0.09) and all-cause hospitalisation (p=0.82) between rosuvastatin and placebo | ||
| Antiplatelet therapy | |||||||
| Ekström (2013; national Swevedox register) [119] | Prospective, national, multicentre (n=2249) | 4 years prior to baseline | Individuals aged ≥45 years with physician-diagnosed COPD treated with LTOT | All dispensed prescriptions in outpatient care in Sweden after July 01, 2005 | Comorbidity and in-hospital time | Patients treated with antiplatelet drugs had higher BMI and more CVD, diabetes mellitus and renal failure than patients not on antiplatelets The use of antiplatelet drugs was associated with decreased mortality (HR 0.86 (95% CI 0.75–0.99), p=0.030) | |
| Harrison (2014; EXODUS cohort) [120] | Observational, cohort, multicentre (n=1343) | 1 year | Individuals >40 years old with spirometry-confirmed COPD admitted to hospital between 2009 and 2011 with AECOPD | All COPD and CV medications | 1-year all-cause mortality | Antiplatelet therapy was correlated with a reduction in 1-year mortality (OR 0.63 (95% CI 0.47–0.85), p=0.003) | Antiplatelet therapy was not correlated with a reduction in hospital mortality (p=0.124), CV hospitalisation (p=0.097) or CV death (p=0.311) |
| Other CV medications | |||||||
| Herrin (2013) [121] | Observational, cohort (n=7104) | Receiving care between January 2001 and December 2006 Follow-up April 2009 | Individuals with COPD and hypertension prescribed with two antihypertensive medications | Thiazide diuretic plus β-blocker Thiazide diuretic plus ACEI/ARB Thiazide diuretic plus CCB β-blocker plus ACEI/ARB | CHF (time to first event requiring hospitalisation) | Choice of antihypertensive medications in combination with a thiazide diuretic had no significant effect on the risk of COPD exacerbations | |
ACE: angiotensin-converting enzyme; ACEI: ACE inhibitor; AECOPD: acute exacerbation of COPD; ARB: angiotensin receptor blocker; ARF: acute respiratory failure; BMI: body mass index; CAD: coronary artery disease; CAT: COPD Assessment Test; CCB: calcium channel blocker; CHF: congestive heart failure; CRP: C-reactive protein; CT: computed tomography; CVD: cardiovascular disease; ER: emergency room; FEV1: forced expiratory volume in 1 s; FVC: forced vital capacity; GOLD, Global Initiative for Chronic Obstructive Lung Disease; HF: heart failure; HR: hazard ratio; hsCRP: high-sensitivity C-reactive protein; IHD: ischaemic heart disease; IRR: incidence risk ratio; LTOT: long-term oxygen therapy; LVEF: left-ventricular ejection fraction; MI: myocardial infarction; NHS: National Health Service; NSAID: non-steroidal anti-inflammatory drug; OR: odds ratio; PAP: pulmonary arterial pressure; PImax: maximal inspiratory pressure; PH: pulmonary hypertension; PVR: pulmonary vascular resistance; PvO2: mixed venous oxygen tension; RAAS: renin–angiotensin–aldosterone system; SABA: short-acting β2-agonist; TLC: total lung capacity; VA: Veterans Affairs. #: β-agonist, inhaled corticosteroid, tiotropium or ipratropium; ¶: defined by use of supplemental oxygen, systemic glucocorticoids or antibiotic therapy, or presentation to the emergency department or hospitalisation.